Bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis

Sustained intracellular Ca2+ overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol-induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion. Orai1 is a plasma membrane Ca2+ channel that mediates extracellular Ca2+ influx upon endoplasmic reticu...

Teljes leírás

Elmentve itt :
Bibliográfiai részletek
Szerzők: Pallagi Petra
Görög Marietta
Papp Noémi
Madácsy Tamara
Varga Árpád
Crul Tim
Szabó Viktória
Molnár Melinda
Dudás Krisztina
Grassalkovich Anna
Szederkényi Edit
Lázár György ifj
Venglovecz Viktória
Hegyi Péter
Maléth József
Dokumentumtípus: Cikk
Megjelent: 2022
Sorozat:JOURNAL OF PHYSIOLOGY-LONDON 600 No. 7
Tárgyszavak:
doi:10.1113/JP282203

mtmt:32624114
Online Access:http://publicatio.bibl.u-szeged.hu/23447
Leíró adatok
Tartalmi kivonat:Sustained intracellular Ca2+ overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol-induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion. Orai1 is a plasma membrane Ca2+ channel that mediates extracellular Ca2+ influx upon endoplasmic reticulum Ca2+ depletion. Our results showed that Orai1 is expressed on the luminal plasma membrane of the ductal cells and selective Orai1 inhibition impaired Stim1-dependent extracellular Ca2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. The prevention of sustained extracellular Ca2+ influx protected ductal cell secretory functions in in vitro models and maintained exocrine pancreatic secretion in in vivo AP models. Orai1 inhibition prevents the bile acid-, and alcohol-induced damage of the pancreatic ductal secretion and holds the potential of improving the outcome of acute pancreatitis.Regardless of its etiology, sustained intracellular Ca2+ overload is a well-known hallmark of acute pancreatitis (AP). Toxic Ca2+ elevation induces pancreatic ductal cell damage characterized by impaired ion- and fluid secretion -essential to wash out the protein-rich fluid secreted by acinar cells while maintaining the alkaline intra-ductal pH under physiological conditions- and mitochondrial dysfunction. While prevention of ductal cell injury decreases the severity of AP, no specific drug target has yet been identified in the ductal cells. Although Orai1 -a store operated Ca2+ influx channel- is known to contribute to sustained Ca2+ overload in acinar cells, details concerning its expression and function in ductal cells are currently lacking. In this study, we demonstrate that functionally active Orai1 channels reside dominantly in the apical plasma membrane of pancreatic ductal cells. Selective CM5480-mediated Orai1 inhibition impairs Stim1-dependent extracellular Ca2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. Furthermore, prevention of sustained extracellular Ca2+ influx protects ductal cell secretory function in vitro and decrease pancreatic ductal cell death. Finally, Orai1-inhibition partially restores and maintains proper exocrine pancreatic secretion in in vivo AP models. In conclusion, our results indicate that Orai1 inhibition prevents AP-related ductal cell function impairment and holds the potential of improving disease outcome. Abstract figure legend This article is protected by copyright. All rights reserved.
Terjedelem/Fizikai jellemzők:1631-1650
ISSN:0022-3751